DESCRIPTION: The broad long term objective of the research are to define the molecular regulation of hepatic homeostasis and understand how disruption of this regulation contributes to liver disease. The TGF-beta signaling pathway has been implicated as a key regulator of liver homeostasis by virtue of its ability to regulate extracellular matrix production, inhibit epithelial cell proliferation and promote apoptosis. Excess TGF-beta signaling is associated with the development of hepatic fibrosis and impaired regenerative capacity, while TGF-beta resistance can result in neoplastic progression. Hepatic homeostasis is also highly dependent upon fully functional apoptotic pathways to remove senescent or damaged hepatocytes and counter unscheduled hepatic growth. The specific aims of this proposal are; 1) to determine the importance of TGF-beta signaling in regulating hepatocyte proliferation, 2) to determine the importance of TGF-beta signaling in the regulation of hepatocyte apoptosis, and 3) to determine the importance of apoptosis in maintaining hepatic homeostasis in normal and diseased liver. The research design uses lines of transgenic mice which express either a constitutively active TGF-beta 1 ligand, a dominant-negative TGF-beta type II receptor, or the baculovirus universal caspase inhibitor, p35 in hepatocytes. These lines will be investigated independently or in combination with established transgenic models, to determine how enhanced or ablated TGF-beta signaling impacts on hepatocyte proliferation, progression to hepatocellular carcinoma, and hepatocyte cell death. The p35-expressing mice will be used to address the importance of functional apoptosis in normal and fibrotic liver, and to determine the contribution of compensatory programmed cell death to the control of hepatic hyperplasia and development of neoplasia.